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The putative P-gp inhibitor telmisartan does not affect the transcellular permeability and cellular uptake of the calcium channel antagonist verapamil in the P-glycoprotein expressing cell line MDCK II MDR1.

Saaby L, Tfelt-Hansen P, Brodin B - Pharmacol Res Perspect (2015)

Bottom Line: Zosuquidar (0.4 μmol/L) reduced the efflux ratio (PB-A/PA-B) for verapamil 4.6-1.6.The presence of telmisartan, however, only caused a slight reduction in P-gp-mediated verapamil transport to an efflux ratio of 3.4.Overall, the results of the present in vitro approach indicate, that clinical use of telmisartan as a P-gp inhibitor may not be an effective strategy for increasing brain uptake of verapamil by co-administration with telmisartan.

View Article: PubMed Central - PubMed

Affiliation: Bioneer:FARMA, Faculty of Health and Medical Sciences, University of Copenhagen, Glostrup Hospital Glostrup, Denmark ; Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen Copenhagen, Denmark.

ABSTRACT
Verapamil is used in high doses for the treatment of cluster headache. Verapamil has been described as a P-glycoprotein (P-gp, ABCB1) substrate. We wished to evaluate in vitro whether co administration of a P-gp inhibitor with verapamil could be a feasible strategy for increasing CNS uptake of verapamil. Fluxes of radiolabelled verapamil across MDCK II MDR1 monolayers were measured in the absence and presence of the putative P-gp inhibitor telmisartan (a clinically approved drug compound). Verapamil displayed a vectorial basolateral-to-apical transepithelial efflux across the MDCK II MDR1 monolayers with a permeability of 5.7 × 10(-5) cm sec(-1) compared to an apical to basolateral permeability of 1.3 × 10(-5) cm sec(-1). The efflux could be inhibited with the P-gp inhibitor zosuquidar. Zosuquidar (0.4 μmol/L) reduced the efflux ratio (PB-A/PA-B) for verapamil 4.6-1.6. The presence of telmisartan, however, only caused a slight reduction in P-gp-mediated verapamil transport to an efflux ratio of 3.4. Overall, the results of the present in vitro approach indicate, that clinical use of telmisartan as a P-gp inhibitor may not be an effective strategy for increasing brain uptake of verapamil by co-administration with telmisartan.

No MeSH data available.


Related in: MedlinePlus

(A) The apparent transepithelial permeability of 3H-verapamil (12 μmol/L) in the apical to basolateral direction across MDCK II (MDR1) cells in the presence or absence of telmisartan (TEL, 2.4 μmol/L). Data points represent the mean permeability of three filter supports (N = 3) of six different passages (n = 6). Lines between data points indicate how the data points are paired within each of the six cell passages. The effect of zosuquidar on the A-B transport of verapamil was statistically significant in a paired t-test (P = 0.0465). (B) Efflux ratio for 3H-verapamil (12 μmol/L) across MDCK II (MDR1) cells in the presence or absence of telmisartan (TEL, 2.4 μmol/L). Data points represent the calculated efflux ratios for six individual passages (n = 6). Lines between data points indicate how the data points are paired within each of the six cell passages.
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fig03: (A) The apparent transepithelial permeability of 3H-verapamil (12 μmol/L) in the apical to basolateral direction across MDCK II (MDR1) cells in the presence or absence of telmisartan (TEL, 2.4 μmol/L). Data points represent the mean permeability of three filter supports (N = 3) of six different passages (n = 6). Lines between data points indicate how the data points are paired within each of the six cell passages. The effect of zosuquidar on the A-B transport of verapamil was statistically significant in a paired t-test (P = 0.0465). (B) Efflux ratio for 3H-verapamil (12 μmol/L) across MDCK II (MDR1) cells in the presence or absence of telmisartan (TEL, 2.4 μmol/L). Data points represent the calculated efflux ratios for six individual passages (n = 6). Lines between data points indicate how the data points are paired within each of the six cell passages.

Mentions: The bidirectional transepithelial transport of [3H]-verapamil was measured in the presence and absence of telmisartan in order to investigate whether telmisartan affects the transport of verapamil across MDCK II (MDR1) cells (n = 6, N = 3). A relatively high concentration of 2.4 μmol/L telmisartan was chosen, as pilot experiments showed no effects at low concentrations (data not shown). The presence of telmisartan caused a small and not statistically significant decrease in B-A permeability, from 5.3 ± 0.9 × 10−5 cm sec−1 (n = 6, N = 3) in the absence of telmisartan to 4.9 ± 0.5 × 10−5 cm sec−1 (n = 6, N = 3) in the presence of 2.4 μmol/L telmisartan. Correspondingly, the A-B permeability increased from 1.3 ± 0.2 × 10−5 cm sec−1 (n = 6, N = 3) in the absence of telmisartan to 1.5 ± 0.3 × 10−5 cm sec−1 (n = 6, N = 3) in the presence of telmisartan. A pairwise comparison of the mean A-B permeabilities of verapamil with the corresponding permeabilities in the presence of telmisartan within each cell passage (Fig.3A), showed that the A-B permeability of verapamil was marginally increased in the presence of 2.4 μmol/L of telmisartan in five out of six passages. In a paired t-test, the observed increase in A-B permeability was statistically significant at a confidence level of 0.05 (P = 0.0465). Similarly, by plotting the efflux ratios of [3H]-verapamil in the presence and absence of 2.4 μmol/L telmisartan shows that the efflux ratio was lower in the presence of telmisartan in five out of six passages (Fig.3B). However, the observed decrease in [3H]-verapamil efflux ratio was not statistically significant at a confidence level of 0.05. The effects of telmisartan on verapamil efflux thus indicate that telmisartan may cause a minor inhibition of the transepithelial efflux of [3H]-verapamil in MDCK II (MDR1) cell monolayers. The amount of [3H]-verapamil present in cells after a transepithelial transport in the A-B direction was measured in order to evaluate the influence of telmisartan and zosuquidar on cellular uptake of [3H]-verapamil (Fig.4). In the presence of 2.4 μmol/L telmisartan, the amount of [3H]-verapamil present in cells and filter supports was increased to 0.24 ± 0.02 nmol cm−2 (n = 3, N = 3) from 0.19 ± 0.02 nmol cm−2 in the absence of telmisartan (P < 0.0001) (n = 6, N = 3). In the presence of 0.4 μmol/L zosuquidar, the amount of [3H]-verapamil present in cells and filter supports was increased to 0.32 ± 0.02 nmol cm−2 (P < 0.0001) (n = 3, N = 3). In other words, both telmisartan and zosuquidar, at concentrations of 2.4 and 0.4 μmol/L, respectively, increased the uptake of [3H]-verapamil into MDCK II (MDR1) cells, consistent with a role as P-gp inhibitors. The concentration of verapamil in the presence of telmisartan increased by ∼26% as compared to the untreated control, whereas the concentration of verapamil in the presence of zosuquidar increased by ∼68%.


The putative P-gp inhibitor telmisartan does not affect the transcellular permeability and cellular uptake of the calcium channel antagonist verapamil in the P-glycoprotein expressing cell line MDCK II MDR1.

Saaby L, Tfelt-Hansen P, Brodin B - Pharmacol Res Perspect (2015)

(A) The apparent transepithelial permeability of 3H-verapamil (12 μmol/L) in the apical to basolateral direction across MDCK II (MDR1) cells in the presence or absence of telmisartan (TEL, 2.4 μmol/L). Data points represent the mean permeability of three filter supports (N = 3) of six different passages (n = 6). Lines between data points indicate how the data points are paired within each of the six cell passages. The effect of zosuquidar on the A-B transport of verapamil was statistically significant in a paired t-test (P = 0.0465). (B) Efflux ratio for 3H-verapamil (12 μmol/L) across MDCK II (MDR1) cells in the presence or absence of telmisartan (TEL, 2.4 μmol/L). Data points represent the calculated efflux ratios for six individual passages (n = 6). Lines between data points indicate how the data points are paired within each of the six cell passages.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
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fig03: (A) The apparent transepithelial permeability of 3H-verapamil (12 μmol/L) in the apical to basolateral direction across MDCK II (MDR1) cells in the presence or absence of telmisartan (TEL, 2.4 μmol/L). Data points represent the mean permeability of three filter supports (N = 3) of six different passages (n = 6). Lines between data points indicate how the data points are paired within each of the six cell passages. The effect of zosuquidar on the A-B transport of verapamil was statistically significant in a paired t-test (P = 0.0465). (B) Efflux ratio for 3H-verapamil (12 μmol/L) across MDCK II (MDR1) cells in the presence or absence of telmisartan (TEL, 2.4 μmol/L). Data points represent the calculated efflux ratios for six individual passages (n = 6). Lines between data points indicate how the data points are paired within each of the six cell passages.
Mentions: The bidirectional transepithelial transport of [3H]-verapamil was measured in the presence and absence of telmisartan in order to investigate whether telmisartan affects the transport of verapamil across MDCK II (MDR1) cells (n = 6, N = 3). A relatively high concentration of 2.4 μmol/L telmisartan was chosen, as pilot experiments showed no effects at low concentrations (data not shown). The presence of telmisartan caused a small and not statistically significant decrease in B-A permeability, from 5.3 ± 0.9 × 10−5 cm sec−1 (n = 6, N = 3) in the absence of telmisartan to 4.9 ± 0.5 × 10−5 cm sec−1 (n = 6, N = 3) in the presence of 2.4 μmol/L telmisartan. Correspondingly, the A-B permeability increased from 1.3 ± 0.2 × 10−5 cm sec−1 (n = 6, N = 3) in the absence of telmisartan to 1.5 ± 0.3 × 10−5 cm sec−1 (n = 6, N = 3) in the presence of telmisartan. A pairwise comparison of the mean A-B permeabilities of verapamil with the corresponding permeabilities in the presence of telmisartan within each cell passage (Fig.3A), showed that the A-B permeability of verapamil was marginally increased in the presence of 2.4 μmol/L of telmisartan in five out of six passages. In a paired t-test, the observed increase in A-B permeability was statistically significant at a confidence level of 0.05 (P = 0.0465). Similarly, by plotting the efflux ratios of [3H]-verapamil in the presence and absence of 2.4 μmol/L telmisartan shows that the efflux ratio was lower in the presence of telmisartan in five out of six passages (Fig.3B). However, the observed decrease in [3H]-verapamil efflux ratio was not statistically significant at a confidence level of 0.05. The effects of telmisartan on verapamil efflux thus indicate that telmisartan may cause a minor inhibition of the transepithelial efflux of [3H]-verapamil in MDCK II (MDR1) cell monolayers. The amount of [3H]-verapamil present in cells after a transepithelial transport in the A-B direction was measured in order to evaluate the influence of telmisartan and zosuquidar on cellular uptake of [3H]-verapamil (Fig.4). In the presence of 2.4 μmol/L telmisartan, the amount of [3H]-verapamil present in cells and filter supports was increased to 0.24 ± 0.02 nmol cm−2 (n = 3, N = 3) from 0.19 ± 0.02 nmol cm−2 in the absence of telmisartan (P < 0.0001) (n = 6, N = 3). In the presence of 0.4 μmol/L zosuquidar, the amount of [3H]-verapamil present in cells and filter supports was increased to 0.32 ± 0.02 nmol cm−2 (P < 0.0001) (n = 3, N = 3). In other words, both telmisartan and zosuquidar, at concentrations of 2.4 and 0.4 μmol/L, respectively, increased the uptake of [3H]-verapamil into MDCK II (MDR1) cells, consistent with a role as P-gp inhibitors. The concentration of verapamil in the presence of telmisartan increased by ∼26% as compared to the untreated control, whereas the concentration of verapamil in the presence of zosuquidar increased by ∼68%.

Bottom Line: Zosuquidar (0.4 μmol/L) reduced the efflux ratio (PB-A/PA-B) for verapamil 4.6-1.6.The presence of telmisartan, however, only caused a slight reduction in P-gp-mediated verapamil transport to an efflux ratio of 3.4.Overall, the results of the present in vitro approach indicate, that clinical use of telmisartan as a P-gp inhibitor may not be an effective strategy for increasing brain uptake of verapamil by co-administration with telmisartan.

View Article: PubMed Central - PubMed

Affiliation: Bioneer:FARMA, Faculty of Health and Medical Sciences, University of Copenhagen, Glostrup Hospital Glostrup, Denmark ; Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen Copenhagen, Denmark.

ABSTRACT
Verapamil is used in high doses for the treatment of cluster headache. Verapamil has been described as a P-glycoprotein (P-gp, ABCB1) substrate. We wished to evaluate in vitro whether co administration of a P-gp inhibitor with verapamil could be a feasible strategy for increasing CNS uptake of verapamil. Fluxes of radiolabelled verapamil across MDCK II MDR1 monolayers were measured in the absence and presence of the putative P-gp inhibitor telmisartan (a clinically approved drug compound). Verapamil displayed a vectorial basolateral-to-apical transepithelial efflux across the MDCK II MDR1 monolayers with a permeability of 5.7 × 10(-5) cm sec(-1) compared to an apical to basolateral permeability of 1.3 × 10(-5) cm sec(-1). The efflux could be inhibited with the P-gp inhibitor zosuquidar. Zosuquidar (0.4 μmol/L) reduced the efflux ratio (PB-A/PA-B) for verapamil 4.6-1.6. The presence of telmisartan, however, only caused a slight reduction in P-gp-mediated verapamil transport to an efflux ratio of 3.4. Overall, the results of the present in vitro approach indicate, that clinical use of telmisartan as a P-gp inhibitor may not be an effective strategy for increasing brain uptake of verapamil by co-administration with telmisartan.

No MeSH data available.


Related in: MedlinePlus